Clefts of the lip and palate (CLP) are one of the most common craniofacial anomalies, with a rate of 1:650 in the United States population. Over 250 genetically based syndromes exist which include cleft lip or palate as a feature of their clinical presentation. Since the fall of 1993, we have been collaborating with the Lancaster Cleft Palate Clinic in Lancaster, PA. This project is a large- scale molecular epidemiological study, involving the comprehensive mapping of highly informative DNA markers, utilizing the clinical population from the Lancaster Cleft Palate Clinic and affiliated clinics. In the past year we completed recruitment efforts at Washington University, St. Louis and at the University of North Carolina, Chapel Hill. Semiautomated gene mapping technologies developed by our group in ongoing CLP studies are being applied to map genes responsible for clefting. We completed molecular marker typing for several candidate regions based on previous reports in the literature and are initiating statistical analyses on these regions. Preliminary results indicate support for a region of chromosome 2 in the vicinity of the transforming growth factor alpha gene. We have completed the laboratory phase of a scan of the entire human genome using a sample based on Lancaster families collected by the end of 1996, and are beginning the computerized scoring component of these gel analyses, with statistical analyses planned for early in the following year. We also completed a small statistical analysis project aimed at evaluating the bias and degree of reproducibility of five raters making 12 craniofacial measurements as part of our routine clinical evaluation of cleft-affected subjects and their families. We are conducting analyses of a mouse model of teratogen-induced clefting and identified several chromosomal regions which may contain clefting susceptibility loci. We plan to continue gene mapping laboratory and statistical analyses to complete a scan of the entire genome in the ongoing collection of simplex and multiplex cleft lip and palate families. We will also be initiating statistical analyses of correlated risk factor phenotypes such as smoking and craniofacial size measurements. Our complimentary mouse studies will involve collection of additional data with the goal of identifying specific genes involved in teratogen-induced clefting susceptibility in the mouse, followed by subsequent analyses in our human study subjects.